US7423040B2 - Stable crystalline form of bifeprunox mesylate, dosage forms thereof and methods for using same - Google Patents

Stable crystalline form of bifeprunox mesylate, dosage forms thereof and methods for using same Download PDF

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US7423040B2
US7423040B2 US11/354,652 US35465206A US7423040B2 US 7423040 B2 US7423040 B2 US 7423040B2 US 35465206 A US35465206 A US 35465206A US 7423040 B2 US7423040 B2 US 7423040B2
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biphenyl
piperazinyl
benzoxazolone
ylmethyl
plasma
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US20060194812A1 (en
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Irene Eijgendaal
Gerrit Klein
Maria J. L. Terhorst-Van Amstel
Klaas Zwier
Nico Bruins
Hendrikus T. Rigter
Erik Gout
Caroline Boon
Michiel H. De Vries
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Abbott Healthcare Products BV
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Solvay Pharmaceuticals BV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present disclosure relates to stable polymorphic forms of the compound 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate, methods for the preparation of such polymorphic forms, pharmaceutical dosage forms comprising said polymorphic forms, and methods for using said pharmaceutical dosage forms for the treatment of various disorders such as, CNS disorders.
  • the mesylate salt of the compound 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate (INNM bifeprunox mesylate) has the formula
  • hydrochloric acid salt of this compound (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone (bifeprunox) is described and claimed in WO97/36893 and the monomethanesulfonate salt is described and claimed in W002/066449.
  • the direct formation of the monomethanesulfonate salt by the reaction between the reactive mesylate ester of N,N,N-bis(2-ethanol)-m-phenylbenzyl amine and 7-amino-2(3H)-benzoxazolone is disclosed.
  • polymorphs ⁇ and ⁇ are metastable, and therefore may have drawbacks when used in a pharmaceutical formulation.
  • the unpredictable formation of one of the two polymorphs ⁇ and ⁇ or a mixture thereof is also undesirable. It would be desirable, therefore, to provide a stable crystalline form of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate for pharmaceutical use which can be consistently produced.
  • 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3monomethanesulfonate also has another crystalline polymorphic form (referred to below as polymorph ⁇ (alpha)) which does not have the disadvantages of the aforementioned polymorphs.
  • polymorph ⁇ alpha
  • This crystalline form of bifeprunox mesylate is more thermodynamically stable.
  • Polymorphic form ⁇ does not undergo conversion, even at high atmospheric humidity or higher temperature.
  • this crystalline form crystallizes in the form of large crystals which can be easily filtrated and have a high purity. Therefore this polymorph ⁇ is particularly suitable for the formulation of bifeprunox mesylate in a solid form, if desired after particle size reduction.
  • the present disclosure provides the polymorphic ⁇ form of bifeprunox mesylate at various levels of purity.
  • the present disclosure provides pharmaceutical dosage forms comprising the polymorphic a form of bifeprunox mesylate.
  • the present disclosure provides methods for using said dosage forms for treatment or prevention of various diseases and disorders.
  • FIG. 1 shows an XRPD pattern of polymorphic form a of bifeprunox mesylate.
  • FIG. 2 shows a DSC trace of polymorphic form a of bifeprunox mesylate.
  • FIG. 3 shows an IR (ATR) spectrum of polymorphic form a of bifeprunox mesylate.
  • FIG. 4 shows a 13 C solid state NMR spectrum of polymorphic form a of bifeprunox mesylate.
  • FIG. 5 shows configuration of polymorphic form a of bifeprunox mesylate derived from X-ray crystallography.
  • FIG. 6 shows an XRPD pattern of polymorphic form ⁇ of bifeprunox mesylate.
  • FIG. 7 shows a DSC trace of polymorphic form ⁇ of bifeprunox mesylate.
  • FIG. 8 shows an IR (ATR) spectrum of polymorphic form ⁇ of bifeprunox mesylate.
  • FIG. 9 shows a 13 C solid state NMR spectrum of polymorphic form ⁇ of bifeprunox mesylate.
  • FIG. 10 shows configuration of polymorphic form ⁇ of bifeprunox mesylate derived from X-ray crystallography.
  • FIG. 11 shows an XRPD pattern of polymorphic form ⁇ of bifeprunox mesylate.
  • FIG. 12 shows a DSC trace of polymorphic form ⁇ of bifeprunox mesylate.
  • FIG. 13 shows an IR (ATR) spectrum of polymorphic form ⁇ of bifeprunox mesylate.
  • FIG. 14 shows a 13 C solid state NMR spectrum of polymorphic form ⁇ of bifeprunox mesylate.
  • FIG. 15 shows configuration of polymorphic form ⁇ of bifeprunox mesylate derived from X-ray crystallography.
  • the crystalline polymorphic form of bifeprunox mesylate according to the present disclosure is defined by at least one of the following physicochemical parameters:
  • the melting point of polymorphic form ⁇ is 277° C. (DSC heating rate 10 K/min) (see DSC thermogram, FIG. 2 );
  • Table 1 shows characteristic X-ray powder diffractions (XRPD) of forms ⁇ , ⁇ and ⁇ of bifeprunox mesylate.
  • XRPD characteristic X-ray powder diffractions
  • Table 2 shows characteristic IR absorption bands of forms ⁇ , ⁇ and ⁇ of bifeprunox mesylate.
  • FIG. 2 provides a representative IR spectrum of polymorphic form ⁇ of bifeprunox mesylate.
  • Table 2a also shows important IR absorption bands of forms ⁇ , ⁇ and ⁇ of bifeprunox mesylate which can be used to distinguish the three forms.
  • Table 3 shows characteristic 13 C solid state NMR chemical shifts in forms ⁇ , ⁇ and ⁇ of bifeprunox mesylate.
  • FIG. 3 provides a representative 13 C solid state NMR spectrum of polymorphic form a of bifeprunox mesylate.
  • Table 3a also shows important 13 C solid state NMR chemical shifts bands of forms ⁇ , ⁇ and ⁇ of bifeprunox mesylate which can be used to distinguish the three forms.
  • Table 4 shows relevant Single Crystal X-ray Diffraction data collection parameters for the crystal structure determination of forms ⁇ , ⁇ and ⁇ of bifeprunox mesylate.
  • Table 5 shows atomic coordinates ( ⁇ 10 4 ) and equivalent isotropic displacement parameters ( ⁇ 2 ⁇ 10 3 ) of crystal structure of form a of bifeprunox mesylate.
  • U(eq) is defined as one third of the trace of the orthogonalized U ij tensor.
  • Table 6 shows atomic coordinates ( ⁇ 10 4 ) and equivalent isotropic displacement parameters ( ⁇ 2 ⁇ 10 3 ) of crystal structure of form ⁇ of bifeprunox mesylate.
  • U(eq) is defined as one third of the trace of the orthogonalized U ij tensor.
  • Table 7 shows atomic coordinates ( ⁇ 10 4 ) and equivalent isotropic displacement parameters ( ⁇ 2 ⁇ 10 3 ) of crystal structure of form ⁇ of bifeprunox mesylate.
  • U(eq) is defined as one third of the trace of the orthogonalized U ij tensor.
  • the polymorphic form a differs substantially from the forms ⁇ and ⁇ in its physicochemical parameters: DSC melting behavior, X-ray diffraction pattern, IR spectrum and solid state 13 C-NMR spectrum.
  • the physicochemical parameters of the forms ⁇ and ⁇ are given in Tables 1-4, 6 and 7 and FIGS. 6-15 .
  • the present disclosure provides bifeprunox mesylate in which at least about 50 percent by weight (wt. %), at least about 60 wt. %, at least about 70 wt. %, at least about 80 wt. %, at least about 90 wt. %, or at least about 95 wt. % of the bifeprunox mesylate is in the polymorphic ⁇ form. In other embodiment, such embodiments are substantially devoid of any ⁇ or ⁇ polymorphic forms of bifeprunox mesylate. In another embodiment, the bifeprunox mesylate provided by the present disclosure comprises less than 10 wt. %, less than 5 wt.
  • bifeprunox mesylate is in the polymorphic a form.
  • the preparation of the polymorphic form ⁇ is carried out by recrystallization from an organic solvent or a mixture of an organic solvent with water, preferably a mixture of a (C 1 -C 6 ) alcohol and water or a mixture of acetonitrile and water.
  • the solvent is a mixture is 2-propanol and water or a mixture of acetonitrile and water.
  • the solvent is a mixture of acetonitrile and water.
  • the polymorphic form ⁇ can be prepared by making the free base of bifeprunox directly followed by the addition of methane sulphonic acid and crystallization from methylethylketone.
  • the polymorphic form ⁇ and ⁇ according to the present disclosure can be formulated into dosage forms in which the crystalline active substance is present in the solid form by methods known in the art.
  • Examples of said dosage forms are (optionally coated) tablets, capsules, granular aerosols, suppositories and suspensions.
  • Such dosage forms can be prepared by mixing the polymorphic form ⁇ or ⁇ of the active substance with inert pharmaceutically acceptable excipients and carriers.
  • one to a small plurality (e.g. 1 to about 4) of dosage units of a composition of the present disclosure comprise about 0.05 to about 40 mg, about 0.75 to about 35 mg, about 0.1 to about 30 mg or about 0.125 to about 20 mg of bifeprunox mesylate (in ⁇ , ⁇ , and/or ⁇ form) per dosage unit.
  • a dosage unit can comprise 0.125 mg, 1 mg, 5 mg, 10 mg, or 20 mg of bifeprunox mesylate.
  • compositions of the present disclosure can comprise one or more pharmaceutical excipients.
  • suitable excipients include suspending agents (for example, gums, xanthans, cellulosics and sugars), humectants (for example, sorbitol), solubilizers (for example, ethanol, water, PEG and propylene glycol), surfactants (for example, sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives, antioxidants (for example, parabens, and vitamins E and C), anti-caking agents, coating agents, chelating agents (for example, EDTA), stabilizers, antimicrobial agents, antifungal or antibacterial agents (for example, parabens, chlorobutanol, phenol, sorbic acid), isotonic agents (for example, sugar, sodium chloride), thickening agents (for example, methyl cellulose), flavoring agents (for example, chocolate, thalmantin, as
  • One illustrative dosage form comprises, apart from the milled and sieved active substance (bifeprunox as described herein), lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (for example, type A), sodium stearyl fumarate and optionally colloidal anhydrous silica.
  • lactose is present in an amount of about 20% to about 90% by weight, about 70% to about 90% by weight, or about 75% to about 85% by weight, based on the total weight of the tablet core.
  • Microcrystalline cellulose is present in an amount of about 5% to about 90% by weight, about 10% to about 15% by weight, or about 11% to about 12% by weight, based on the total weight of the tablet core.
  • Sodium starch glycolate e.g.
  • type A is present in an amount of about 0.1% to about 2.5% by weight, about 0.3% to about 0.7% by weight, or about 0.5% by weight, based on the total weight of the tablet core.
  • Sodium stearyl fumarate is present in an amount of about 0.1% to about 1.5% by weight, about 0.6% to about 1.3% by weight, or about 1.0% by weight, based on the total weight of the tablet core.
  • Colloidal anhydrous silica is optionally added to the formulation in order to improve the flow properties of the powder. If desired, colloidal anhydrous silica is typically present in an amount of about 0.05% to about 0.5% by weight or about 0.4% by weight, based on the total weight of the tablet core.
  • the amount of optional coating is about 2.0% to about 5.0% by weight, about 3.0% to about 4.0% by weight, or about 3.5% by weight, based on the total weight of the tablet core.
  • the present disclosure relates to a method of producing the formulation described above, wherein the active substance having the polymorphic form ⁇ or ⁇ according to the present disclosure is milled and subsequently using a suitable mixer (e.g. an orbital screw mixer (Nauta mixer) or a combination of a diffusion mixer (bin blender) with a rotating impeller mill (quadro co-mill)) with lactose monohydrate, microcrystalline cellulose, sodium starch glycolate type A, sodium stearyl fumarate and optionally with colloidal anhydrous silica.
  • a suitable mixer e.g. an orbital screw mixer (Nauta mixer) or a combination of a diffusion mixer (bin blender) with a rotating impeller mill (quadro co-mill)
  • lactose monohydrate e.g. an orbital screw mixer (Nauta mixer) or a combination of a diffusion mixer (bin blender) with a rotating impeller mill (quadro co-mill)
  • a suitable mixer e.g
  • any suitable pressure can be used, for example about 200 MPa to about 400 MPa, about 250 MPa to about 350 MPa, or about 300 MPa.
  • the dosage form is optionally coated with a color and taste coating by spraying of a coating suspension onto the tablet core using any suitable coating equipment (e.g. a perforated pan coater or a fluidized bed coater).
  • compositions comprising the polymorphic form a and/or ⁇ according to the present disclosure can be administered to a subject, for example a human subject, in need thereof.
  • a subject for example a human subject
  • Such compositions are useful for, inter alia, the treatment of humans suffering from psychotic disorders (e.g. schizophrenia) or Parkinson's disease.
  • a composition of the present disclosure upon oral administration of a composition of the present disclosure to a human subject (or a plurality thereof), for example a fasted adult human subject, the subject exhibits a plasma T max (or a mean plasma T max if administered to a plurality of human subjects) of bifeprunox within about 3 hours, within about 2.8 hours, within about 2.7 hours, within about 2.6 hours, within about 2.5 hours, within about 2.4 hours, within about 2.3 hours, within about 2.2 hours, within about 2.1 hours or within about 2 hours.
  • T max refers to the time at which the maximum plasma concentration of bifeprunox is attained following administration of bifeprunox mesylate to the subject.
  • a composition of the present disclosure upon oral administration of a composition of the present disclosure to a human subject (or a plurality thereof), for example a fasted adult human subject, the subject exhibits a plasma C max (or a mean C max if administered to a plurality of human subjects) of bifeprunox of at least about 0.1 ng/ml, at least about 0.12 ng/ml, at least about 0.13 ng/ml, at least about 0.14 ng/ml, at least about 0.15 ng/ml, at least about 0.16 ng/ml, at least about 0.17 ng/ml, at least about 0.18 ng/ml, at least about 0.19 ng/ml, at least about 0.2 ng/ml, at least about 0.21 ng/ml, at least about 0.22 ng/ml, at least about 0.23 ng/ml, at least about 0.24 ng/ml, at least about 0.25 ng/ml, at least about 0.26 ng/ml,
  • a composition of the present disclosure upon oral administration of a composition of the present disclosure to a human subject (or a plurality thereof), for example a fasted adult human subject, the subject exhibits a plasma AUC 0-24 (or a mean plasma AUC 0-24 if administered to a plurality of human subjects) of bifeprunox of at least about 0.9 hr ⁇ ng/ml, 1.0 hr ⁇ ng/ml, 1.1 hr ⁇ ng/ml, 1.2 hr ⁇ ng/ml, 1.3 hr ⁇ ng/ml, or 1.4 hr ⁇ ng/ml.
  • AUC 0-24 refers to the area under the plasma concentration versus time curve for the twenty-four hour period after administration.
  • composition of the present disclosure upon oral administration of a composition of the present disclosure to a human subject (or a plurality thereof), for example a fasted adult human subject, the subject exhibits at least one of:
  • the crude product was suspended in 2000 ml 96% ethanol, heated till reflux and refluxed under stirring for about 15 minutes until a clear solution was obtained.
  • the solution was cooled to 25-30° C. in about 1 hour, while stirring slowly, further cooled to 0-5° C. and stirred at this temperature for an additional hour.
  • the solid was filtered off, washed twice with 250 ml of cold 96% ethanol, and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 78%.
  • a mixture was prepared of 123.4 g of diethanolamine, 100 ml of water and 100 ml of methylethylketone (MEK) and 500 ml of methyl t-butyl ether while stirring under a mild nitrogen purge 124.75 g of. 3-(bromomethyl)-1,1′-biphenyl was added together with 750 ml of methyl t-butyl ether.
  • the mixture was heated to reflux and refluxed for 18 hours, followed by cooling till room temperature. Thereafter the mixture was washed once with 375 ml of 2N NaOH and four times with 375 ml of water. The combined 2N NaOH and water layers were extracted with 750 ml of methyl t-butyl ether.
  • the mixture was further cooled down to 0-5° C. and stirred at this temperature for another hour.
  • the solid was filtered off and, washed twice with 75 ml of cold methylethylketone, and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 76%.
  • Example 1g 50 g of bifeprunox mesylate prepared crude as described in Example 1g was suspended in a mixture of 875 ml of acetonitrile and 250 ml of water under nitrogen purge. 375 ml of acetonitrile was added and the reaction mixture was heated till reflux. 500 ml of solvent was distilled off and 500 ml of acetonitrile were added and this procedure was repeated for a second time. After distilling another 500 ml of solvent the mixture was cooled down to room temperature in 120 minutes. The mixture was further cooled down to 0-5° C. and stirred for 120 minutes at this temperature. The formed crystals were filtered off and washed twice with acetonitrile. The isolated crystals were dried at 50° C. and 100 mbar under a mild nitrogen purge. Yield 85.6%.
  • methylethylketone layer was filtered through a 1 ⁇ m filter into a clean vessel, after which the filter was rinsed with 25 ml of methylethylketone. Methylethylketone was distilled off until a volume of about 130 ml was reached, 200 ml of methylethylketone was added and again methylethylketone was distilled off to reach a volume of 175 ml.
  • lactose a high shear mixer
  • 125 g of bifeprunox mesylate in its polymorphic form ⁇ was sieved and added.
  • the composition was mixed with a high shear mixer (e.g. Collette Gral 10 or Collette Gral 75) until it was homogenous (approximately 4 minutes).
  • 24 g of a disintegrant e.g. sodium starch glycolate USP-NF such as Primojel®
  • a lubricant e.g. sodium stearyl fumarate such as PRUV®
  • the powder was filled into capsules size 0, 240 mg per capsule by means of a capsule filling machine (e.g. Zanasi LZ 64 or Zanasi RM63 plug filler). Approximately 10,000 filled capsules were obtained.
  • Tablets with a strength of 10 mg were prepared according to the following procedures (required quantities are given in Table 8).
  • One third of the given amount of lactose monohydrate was sieved and filled into a high shear mixer and mixed during 5 minutes.
  • the required amount of milled bifeprunox mesylate in its polymorphic form ⁇ was added to the mixture, together with 0.100 kg sodium starch glycolate, type A, 2.32 kg microcrystalline cellulose and the remainder of the lactose monohydrate.
  • the composition was mixed with a high shear mixer (e.g. Collette Gral 10 or Collette Gral 75) until it was homogenous (approximately 10 minutes).
  • the final product was compressed with 300 MPa into tablets.
  • the product was coated using 15% m/m of the indicated Opadry II HP water suspension to 3.5% of the core weight.
  • Table 8 shows the amount of active ingredient and auxiliary materials used in a large scale production of 10 mg bifeprunox mesylate tablets.
  • XRPD patterns were measured on a diffractometer using monochromatic CuK ⁇ radiation (tube voltage 40 kV, tube current 40 mA) at room temperature. IR spectra were recorded on a Fourier transform IR spectrometer in attenuated total reflectance (silicon crystal) with a spectral resolution of 2 cm ⁇ 1 using a mercury cadmium telluride detector.
  • Melting points were determined on a DSC apparatus as onset temperatures of the melting endotherm using 40 ⁇ L aluminum crucibles with a pierced lid. Temperature program: heating from 25° C. up to 300° C. with 10 K min ⁇ 1 . N 2 atmosphere at a flow of 80 mL min ⁇ 1 .
  • the solid state 13 C NMR spectra were obtained using the cross-polarisation magic-angle spinning (CP/MAS) accessory on a Bruker AM300 instrument (contact time of 4 ms, recycle delay 3 s, spectral width 30 kHz, 1 H 90° pulse of 6 ⁇ s, spinning rate about 8.5 kHz.
  • CP/MAS cross-polarisation magic-angle spinning
  • Crystals of the alpha ( ⁇ ) form appeared under the microscope as block-shaped, those of the gamma ( ⁇ ) crystal form were plate- or rod-shaped, whereas crystals of the delta ( ⁇ ) crystal form looked block-shaped with rounded edges.
  • a crystal was transferred into the cold nitrogen stream on a rotating anode X-ray diffractometer.
  • the structures were solved by automated direct methods. Hydrogen atoms bonded to nitrogen were located on an electron-density map and their coordinates were included as parameters in the refinement. Other hydrogen atoms were included in the refinement on calculated positions riding on their carrier atoms. All non-hydrogen atoms were refined with anisotropic atomic displacement parameters. Hydrogen atoms were given fixed displacement factors, related to those of their carrier atoms.
  • a single center, open label, randomized, double two-way cross-over study was used to assess the relative bioavailability of a 0.125 mg and a 20 mg (active ingredient amount) capsule formulation ( ⁇ polymorphic form of bifeprunox mesylate) respectively with a 0.125 mg and 20 mg (active ingredient amount) tablet formulation of the a polymorphic form of bifeprunox mesylate after oral administration to healthy male and female volunteers.
  • Capsules and tablets were prepared substantially as described in Examples 5 and 6 with appropriate adjustments for dose and formulation, e.g., capsules or tablets.
  • Treatment started with a single dose of 0.125 mg bifeprunox mesylate as either a capsule or tablet formulation.
  • the first cross-over started on Day 3 when a single dose of 0.125 mg bifeprunox mesylate, in the opposite formulation than that started with, was given.
  • the subjects were uptitrated with the Day 3 formulation over a period of 8 days (Days 5-12).
  • the 20 mg formulation was given for an additional 3 days (Days 13-15), followed by a second cross-over to a 20 mg treatment of the first formulation (capsule or tablet) for four days (Days 16-19).
  • Pharmacokinetic parameters were determined two times for 48 hours starting on Days 1 and 3 (for the single dose pharmacokinetics), and two times for 24 hours starting on Days 15 and 19 (for multiple dose pharmacokinetics). For differences between the test (tablet) and the reference (capsule) treatment, 90% confidence intervals are given for the 0.125 mg and 20 mg treatments. The information for the 0.125 data is extracted out of the Day 1 and Day 3 measurements, while the steady state plasma levels of Day 15 and Day 19 are used for the pharmacokinetic information of the 20 mg regimen.
  • the bioavalability (AUC, C max ) of the 0.125 mg tablet was higher compared to the reference capsule. Compared to the capsule, that tablet also exhibited a faster T max . From 6 hours post administration up to the last measurable plasma concentrations, the average plasma concentration time profiles were nearly congruent for both formulations.
  • the capsule and tablet formulation Following multiple 20 mg doses, no major differences were found between the capsule and tablet formulation.
  • the 90% confidence intervals of the ratio tablet/capsule were within the 80%-125% range.
  • Each of the tablets were placed in a dissolution test under the following conditions: Apparatus: paddle method; Stirring speed: 50 rpm; Amount of test dissolution medium: 900 ml; Temperature of dissolution medium: 37° C. ⁇ 0.5° C.
  • MclLvaine buffer solution pH 3.0
  • Tables 11-16 show dissolution results in each of the above media, respectively. Dissolution testing was performed in triplicate.

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US20080132520A1 (en) * 2006-08-31 2008-06-05 Winsemius Antje A Compositions, kits and methods for administering a titration schedule comprising bifeprunox compounds
US20080286258A1 (en) * 2005-02-18 2008-11-20 Irene Eijgendaal Bifeprunox mesylate maintenance dose compositions and methods for using the same
US20090068290A1 (en) * 2006-08-31 2009-03-12 Michel Bourin Bifeprunox doses for treating schizophrenia
US20100119622A1 (en) * 2008-09-15 2010-05-13 Auspex Pharmaceuticals, Inc. 3h-benzooxazol-2-one modulators of d2 receptor and/or 5-ht1a receptor

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US7435738B2 (en) 2003-08-18 2008-10-14 Solvay Pharmaceuticals, Inc. Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate)
US7405216B2 (en) 2004-08-18 2008-07-29 Solvay Pharmaceuticals, B.V. Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate)
US7423040B2 (en) 2005-02-18 2008-09-09 Irene Eijgendaal Stable crystalline form of bifeprunox mesylate, dosage forms thereof and methods for using same
US7786126B2 (en) 2006-06-16 2010-08-31 Solvay Pharmaceuticals B.V. Combination preparations comprising SLV308 and a dopamine agonist
US8106056B2 (en) 2006-06-16 2012-01-31 Solvay Pharmaceuticals B.V. Combination preparations comprising bifeprunox and a dopamine agonist
KR20090063228A (ko) * 2006-08-31 2009-06-17 솔베이 파마슈티칼스 비. 브이 정신분열증 치료용 비페프루녹스를 위한 적정 계획 및 이에사용하기 위한 키트
EP2377850A1 (de) 2010-03-30 2011-10-19 Pharmeste S.r.l. TRPV1-Vanilloidrezeptorantagonisten mit einem bizyklischen Teil

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US20080286258A1 (en) * 2005-02-18 2008-11-20 Irene Eijgendaal Bifeprunox mesylate maintenance dose compositions and methods for using the same
US7964604B2 (en) * 2005-02-18 2011-06-21 Solvay Pharmaceuticals B.V. Bifeprunox mesylate maintenance dose compositions and methods for using the same
US20110200687A1 (en) * 2005-02-18 2011-08-18 Solvay Pharmaceuticals B.V. Bifeprunox mesylate maintenance dose compositions and methods for using the same
US20080132520A1 (en) * 2006-08-31 2008-06-05 Winsemius Antje A Compositions, kits and methods for administering a titration schedule comprising bifeprunox compounds
US20090068290A1 (en) * 2006-08-31 2009-03-12 Michel Bourin Bifeprunox doses for treating schizophrenia
US20100119622A1 (en) * 2008-09-15 2010-05-13 Auspex Pharmaceuticals, Inc. 3h-benzooxazol-2-one modulators of d2 receptor and/or 5-ht1a receptor

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